Heterocyclic compounds which have useful pharmaceutical utility

ABSTRACT

A compound of formula (I): ##STR1## or a pharmaceutically acceptable salt, ester or amide thereof, or a pharmaceutically acceptable solvate thereof, wherein: 
     Z represents a residue of a substituted or unsubstituted aryl group, 
     A 1  represents a substituted or unsubstituted methylene group or a substituted or unsubstituted ethylene group; 
     A 2  represents a substituted or unsubstituted methylene group or a substituted or unsubstituted ethylene group; 
     providing that at least one of A 1  or A 2  represents a substituted methylene group or a substituted ethylene group, 
     X represents O or NR o  wherein R o  represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, an alkanoyl group substituted or unsubstituted in the alkyl moiety, or an arylalkyl moiety substituted or unsubstituted in the aryl moiety, 
     p represents an integer 2 or 3, and 
     q represents an integer in the range of from 1 to 12; 
     a process for preparing such a compound, a composition comprising such a compound and the use of such a compound in medicine.

This application is a divisional application of application Ser. No.493,351, filed Mar. 14, 1990, now U.S. Pat. No. 5,077,299, which is adivisional application of application Ser. No. 124,902, filed Nov. 24,1987, now U.S. Pat. No. 4,918,083.

This invention relates to a class of novel heterocyclic compounds havingα₂ -adrenoceptor antagonist activity, to a process for preparing suchcompounds, to pharmaceutical compositions containing such compounds andthe use of such compounds and compositions in medicine.

British Patent Application, Publication No. 2021100A and European PatentSpecification, Publication Number 0,072,954 disclose certainheterocyclic compounds which are described as having long lastinganti-hypertensive activity.

A novel class of heterocyclic compounds has now been discovered whichare structurally distinct from the GB 2021100A and EP 0,072,954compounds. The novel heterocyclic compounds surprisingly show good α₂-adrenoceptor antagonist activity and they are therefore of potentialuse in the treatment and/or prophylaxis of hyperglycaemia and/orglaucoma and/or the treatment of hypertension and/or depression and/orfor inhibiting blood platelet aggregation.

Accordingly, the present invention provides a compound of formula (I):##STR2## or a pharmaceutically acceptable salt, ester or amide thereof,or a pharmaceutically acceptable solvate thereof, wherein:

Z represents a residue of a substituted or unsubstituted aryl group,

A¹ represents a substituted or unsubstituted methylene group or asubstituted or unsubstituted ethylene group;

A² represents a substituted or unsubstituted methylene group or asubstituted or unsubstituted ethylene group;

providing that at least one of A¹ or A² represents a substitutedmethylene group or a substituted ethylene group,

X represents O or NR^(o) wherein R^(o) represents a hydrogen atom, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaryl group, an alkanoyl group substituted or unsubstituted in the alkylmoiety, or an arylalkyl moiety substituted or unsubstituted in the arylmoiety,

p represents an integer 2 or 3, and

q represents an integer in the range of from 1 to 12.

Suitably Z represents the residue of a substituted or unsubstituted arylgroup comprising single or fused 5- or 6- membered rings, such as aphenyl, naphthyl, anthracyl or phenanthrenyl group.

Favourably, Z represents the residue of a substituted or unsubstitutedphenyl or naphthyl group.

Preferably, Z represents the residue of a substituted or unsubstitutedphenyl group.

Suitably, A¹ or A² represent a substituted or unsubstituted methylenegroup.

In one preferred form of the invention, A¹ represents a substitutedmethylene group and A² represents an unsubstituted methylene group.

Suitable optional substitutents for any aryl group or aryl moietyinclude up to 5 preferably up to 3, groups selected from halogen, alkyl,alkenyl, alkynyl, phenyl, haloalkyl, hydroxy, alkoxy, arylalkyloxy,amino, mono- and di-alkylamino, aminoalkyl, mono- anddi-alkylaminoalkyl, nitro, carboxy, alkoxycarbonyl, carboxyalkyl,alkoxycarbonylalkyl, alkylcarbonyl or a moiety SO₂ NR^(s) R^(t) whereinR^(s) and R^(t) each independently represent hydrogen or alkyl, or R^(s)and R^(t) together with the nitrogen to which they are attached form asaturated 5- or 6- membered ring.

Suitable optional substituents for any alkyl, alkenyl or alkynyl groupmoiety include those mentioned above in relation to the aryl group.

It will be appreciated that the abovementioned substituents for arylgroups and aryl moieties includes substituents for those aryl groups ofwhich Z represents a residue; aryl group substituents of A¹ or A² andaryl moieties forming aralkyl substituents of A¹ or A² ; aryl groupsrepresented by R^(o) ; and aryl moieties forming part of other groupsrepresented by R^(o).

It will be appreciated that the abovementioned substituents for alkyl,alkenyl or alkynyl groups includes alkyl, alkenyl or alkynylsubstituents for A¹ or A² ; substituents for those alkyl groupsrepresented by R^(o) and substituents for those alkyl moieties formingpart of other groups represented by R^(o).

A preferred substituent for Z is a halogen atom, especially a fluorineor chlorine atom.

Suitable substituents for A¹ or A² include up to four groups selectedfrom substituted or unsubstituted alkyl; substituted or unsubstitutedalkenyl; substituted or unsubstituted alkynyl; substituted orunsubstituted aryl or aralkyl.

Favoured substituents for A¹ or A² include alkyl, substituted orunsubstituted phenyl or benzyl.

A preferred substituent for A¹ or A² is alkyl, especially C₁₋₆ alkyl,and in particular C₁₋₄ alkyl, such as methyl, ethyl or iso- propyl.

A preferred substituent for A¹ or A² is a phenyl group or a substitutedphenyl group, suitably substituted with a halogen atom, especially afluorine or a chlorine atom, an alkyl group, especially a C₁₋₆ alkylgroup and in particular a C₁₋₄ alkyl group such as a methyl group, analkoxy group, especially a C₁₋₆ alkoxy group and in particular a C₁₋₄alkoxy group, such as a methoxy group.

A preferred substituent for A¹ or A² is a benzyl group.

Suitably, X represents NR^(o).

Suitably, R^(o) represents hydrogen, alkyl or alkanoyl.

Preferably, R^(o) represents hydrogen.

Suitably, q represents an integer in the range of from 1 to 6.

In one aspect the present invention provides a compound, falling whollywithin the scope of formula (I), of formula (II): ##STR3## or apharmaceutically acceptable salt, ester or amide thereof, or apharmaceutically acceptable solvate thereof, wherein:

Z, X, p and q are as defined in relation to formula (I), R and R¹ eachindependently represents hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted aryl or aralkyl substituted orunsubstituted in the aryl moiety; providing that only one of R and R¹represents hydrogen.

Suitably, R and R¹ each independently represents hydrogen, alkyl,substituted or unsubstituted aryl or aralkyl providing that only one ofR and R¹ represents hydrogen.

Suitably, R and R¹ each independently represents hydrogen, alkyl orsubstituted or unsubstituted aryl, providing that only one of R and R¹represents hydrogen.

Favourably, R and R¹ each independently represent hydrogen, alkyl,substituted or unsubstituted phenyl or a benzyl group providing thatonly one of R and R¹ represents hydrogen.

Preferably R¹ represents hydrogen.

When R or R¹ represents an alkyl group it is preferably an unsubstitutedalkyl group, in particular an unsubstituted C₁₋₆ alkyl group, such asmethyl, ethyl or propyl.

A preferred aryl group represented by R or R¹ is a substituted orunsubstituted phenyl group.

A preferred aralkyl group represented by R or R¹ is a benzyl group.

Favourably, R represents alkyl, especially C₁₋₆ alkyl, and in particularC₁₋₄ alkyl, such as methyl, ethyl, or propyl and R¹ represents hydrogen.An example of a propyl group is an iso-propyl group.

Favourably, R represents a phenyl group or a substituted phenyl groupand R¹ represents hydrogen.

Favourably, R represents a benzyl group and R¹ represents hydrogen.

Thus, in particular R represents alkyl, substituted or unsubstitutedphenyl or a benzyl group and R¹ represents hydrogen.

Suitable substituents for R and R¹ include halogen, hydroxy, alkyl,alkoxy, carboxy, alkoxycarbonyl, aminocarbonyl, mono- and di-alkylaminocarbonyl or a group SO₂ NHR^(s) wherein R^(s) representsalkyl.

Preferably, R or R¹ independently represents hydrogen; C₁₋₆ alkyl,especially methyl, ethyl or propyl; phenyl; halophenyl, especiallychlorophenyl or fluorophenyl; alkylphenyl, especially C₁₋₆ alkylphenylsuch as methylphenyl; alkoxyphenyl, especially C₁₋₆ alkoxyphenyl such asmethoxyphenyl or benzyl; providing that only one of R¹ and R₂ representshydrogen.

Thus in particular R represents C₁₋₆ alkyl, especially methyl, ethyl orpropyl; phenyl; halophenyl, especially chlorophenyl or fluorophenyl;alkylphenyl, especially C₁₋₆ alkylphenyl such as methylphenyl;alkoxyphenyl, especially C₁₋₆ alkoxyphenyl such as methoxyphenyl orbenzyl and R¹ represents hydrogen.

Most preferably R or R¹ independently represent hydrogen; methyl; ethyl;propyl; phenyl; monochlorophenyl, especially 3- or 4- chlorophenyl;monofluorophenyl, especially 4-fluorophenyl; monoalkylphenyl, especiallymono-C₁₋₆ -alkylphenyl such as 4-methylphenyl; monoalkoxyphenyl,especially mono C₁₋₆ -alkoxyphenyl, such as 4-methoxyphenyl or benzyl.

Thus in particular R represents hydrogen; methyl; ethyl; propyl; phenyl;monochlorophenyl, especially 3- or 4- chlorophenyl; monofluorophenyl,especially 4-fluorophenyl; monoalkylphenyl, especially mono-C₁₋₆alkylphenyl such as 4-methylphenyl; monoalkoxyphenyl, especiallymono-C₁₋₆ -alkoxyphenyl, such as 4-methoxyphenyl or benzyl and R¹represents hydrogen.

In an especially favoured aspect, R represents methyl, ethyl, orisopropyl, especially methyl or ethyl, and R¹ represents hydrogen.

In an especially preferred aspect R represents phenyl, 4-fluorophenyl,3-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl orbenzyl and R¹ represents hydrogen.

In the most preferred aspect R represents methyl or ethyl and R¹represents hydrogen.

Preferably X represents NH.

Preferably, p represents the integer 2.

Preferably, q represents the integer 1.

The present invention particularly provides a group of compounds,falling within the scope of formula (I), of formula (III); ##STR4## or apharmaceutically acceptable salt, ester or amide thereof, or apharmaceutically acceptable solvate thereof, wherein R, R¹, X, p and qare as defined above and R₂ and R³ each independently representshydrogen, alkyl, amino, mono- or di- alkyl amino, hydroxy, alkoxy,carboxy, or a halogen atom.

Suitably, R₂ or R³ independently represent hydrogen or halogen.

Suitably, R₂ represents halogen, especially fluorine or chlorine.

Suitably, R³ represents hydrogen.

Preferably, R₂ represents halogen, especially fluorine or chlorine andR³ represents hydrogen.

In a further preferred aspect R₂ and R³ both represent hydrogen.

Certain of the compounds of the present invention may exist in one ormore stereoisomeric forms. The present invention encompasses all suchisomeric forms whether free from other isomers or admixed with any otherisomer in any proportion, and thus includes racemic mixtures ofenantiomers.

Suitable pharmaceutically acceptable salts of the compound of formula(I) include acid addition salts, salts of carboxy groups and salts ofhydroxy groups, especially acid addition salts.

Suitable pharmaceutically acceptable acid addition salts of compound (I)include pharmaceutically acceptable inorganic salts such as thesulphate, nitrate, phosphate, borate, hydrochloride and hydrobromide andpharmaceutically acceptable organic acid addition salts such as acetate,tartrate, maleate, citrate, succinate, benzoate, ascorbate,methane-sulphonate, α-keto glutarate, α-glycerophosphate, andglucose-1-phosphate. Preferably the acid addition salt is ahemisuccinate, hydrochloride, α-ketoglutarate, α-glycerophosphate orglucose-1-phosphate, in particular the hydrochloride salt, including thedihydrochloride.

Suitable pharmaceutically acceptable salts of carboxy groups includemetal salts, such as for example aluminium, alkali metal salts such assodium or potassium, alkaline earth metal salts such as calcium ormagnesium and ammonium or substituted ammonium salts, for example thosewith lower alkylamines such as triethylamine, hydroxy-lower alkylaminessuch as 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine ortri-(2-hydroxyethyl) -amine, cycloalkylamines such as bicyclohexylamine,or with procaine, dibenzylpiperidine, N-benzyl-β-phenethylamine,dehydroabietylamine, N,N'-bisdehydroabietylamine, glucamine,N-methylglucamine or bases of the pyridine type such as pyridine,collidine or quinoline.

Suitable pharmaceutically acceptable salts of hydroxyl groups includemetal salts, especially alkali metal salts such as sodium and potassiumsalts.

Suitable pharmaceutically acceptable esters of compounds of formula (I)include esters of carboxy groups and hydroxy groups.

Favoured pharmaceutically acceptable esters are in-vivo hydrolysableesters of carboxy groups and hydroxy groups.

Examples of suitable in-vivo hydrolysable esters of carboxyl groupsinclude those which break down readily in the human body to leave theparent acid or its salt. Suitable ester groups of this type includethose of part formula (i), (ii) and (iii): ##STR5## wherein R^(a) ishydrogen, methyl, or phenyl,

R^(b) is C₁₋₆ alkyl, C₁₋₆ alkoxy or phenyl; or

R^(a) and R^(b) together form a 1,2-phenylene group optionallysubstituted by one or two methoxy groups;

R^(c) represents C₁₋₆ alkylene optionally substituted with a methyl orethyl group

R^(d) and R^(e) independently represent C₁₋₆ alkyl;

R^(f) represents C₁₋₆ alkyl.

Examples of suitable in vivo hydrolysable ester groups include forexample acyloxyalkyl groups such as acetoxymethyl, pivaloyloxy-methyl,α-acetoxyethyl and α-pivaloyloxyethyl groups; alkoxycarbonyloxyalkylgroups, such as ethoxycarbonyl-oxymethyl and α-ethoxycarbonyloxyethyl;dialkylamino-alkyl especially di-loweralkylamino alkyl groups such asaminomethyl or diethylaminoethyl and lactone groups such as phthalidyland dimethoxyphthalidyl.

Suitable in-vivo hydrolysable esters of hydroxyl groups include thoseprovided by C₁₋₆ alkyl carboxylic acids.

Suitable pharmaceutically acceptable amides include amides of formula--CO. NR^(s) R^(t) wherein R^(s) and R^(t) each independently representhydrogen or C₁₋₆ alkyl; or R^(s) and R^(t) together with the nitrogen towhich they are attached represent a saturated 5- or 6- membered ring.

Suitable pharmaceutically acceptable solvates includes hydrates.

When used herein the term "halogen" refers to fluorine, chlorine,bromine and iodine; preferably chlorine.

When used herein the term "in-vivo" hydrolysable ester"relates to apharmaceutically acceptable ester which readily breaks down in the humanor non-human animal body to leave for example in relation to an in-vivohydrolysable ester of a carboxy group the free carboxy group or a saltthereof or for example in relation to an in-vivo hydrolysable ester ofan hydroxy group, the free hydroxy group, or a salt thereof.

When used herein the term "alkyl", "alkenyl", "alkynyl" or "alkoxy"relates to groups having straight or branched chains containing up to 12carbon atoms.

Suitable alkyl groups are C₁₋₁₂ alkyl groups especially C₁₋₆ alkylgroups e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl ortert-butyl groups.

Suitable alkenyl groups are C₂₋₁₂ groups especially C₂₋₆ alkenyl groups.

Suitable alkynyl groups are C₂₋₁₂ alkynyl groups especially C₂₋₆ alkynylgroups.

The present invention also provides a process for the preparation of acompound of formula (I), or a pharmaceutically acceptable salt, ester oramide thereof, or a pharmaceutically acceptable solvate thereof, whichprocess comprises cyclising a compound of formula (IV): ##STR6## whereinZ, A¹, A², p and q are as defined in relation to formula (I), X¹represents O or NH and Y represents OR^(g) wherein R^(g) is hydrogen ora hydroxyl protecting group, or --NHR^(h) wherein R^(h) representshydrogen or a nitrogen protecting group; providing that when X¹ is Othen Y is OR^(g) and when X¹ is NH then Y is NHR^(h) ;

and thereafter if required carrying out one or more of the followingoptional steps:

(i) removing any protecting groups;

(ii) converting a compound of formula (I) into a further compound offormula (I);

(iii) converting a compound of formula (I) into a pharmaceuticallyacceptable salt, ester or amide thereof, or a pharmaceuticallyacceptable solvate thereof;

Preferably, R^(h) represents hydrogen.

A compound of formula (IV) may be prepared by reacting a compound offormula (V): ##STR7## wherein Z, A¹, A² and q are as defined in relationto formula (I) and X² represents CN, or CO₂ R⁴ wherein R⁴ representshydrogen or an alkyl group, with a compound of formula (VI): ##STR8##wherein p is defined in relation to formula (I) and Y represents OR^(g)when X² is --CO₂ R⁴ and Y represents --NR^(h) when X² is CN.

Preferably, Y represents --NR^(h), as defined above, and X² representsCN.

A compound of formula (V) may be prepared by reacting a compound offormula (VII): ##STR9## wherein Z, A¹ and A² are as defined in relationto formula (I) and R^(x) represents a leaving group, with a compound offormula (VIII):

    H.sub.2 N--(CH.sub.2)q-X.sup.2                             (VIII)

or an acid addition salt thereof, preferably a hydrochloride, wherein qand X² are as defined in relation to formula (V).

Suitably, R^(x) represents a halogen atom, preferably a chlorine orbromine atom, especially a bromine atom.

The compounds of formulae (VI) and (VIII) are either known commerciallyavailable compounds or may be prepared using methods analogous to thoseused to prepare such compounds.

The compounds of formula (VII) are either known compounds or may beprepared using methods analogous to those used to prepare knowncompounds: for example by using the methods disclosed in Helv. Chim.Acta, 1977, 60, 2872, J. Chem. Soc., Perkin I, 1972, 2732 and Bull. Soc.Chim. France, 1953, 321.

The cyclisation of compounds of formula (IV) may be carried out underany appropriate conditions, using any suitable solvent system andtemperature range, but usually at an elevated temperature.

Favourably for compounds of formula (I) wherein X represents 0, thecyclisation of the compound of formula (IV) is carried out in thepresence of a dehydrating agent, such as phosphoryl chloride.Conveniently the reaction is carried out in toluene, or any othersuitable solvent, preferably at the reflux temperature of the chosensolvent.

Suitably, for the preparation of compounds of formula (I) wherein Xrepresents NR^(o), the compounds of formula (IV) from the reactionbetween the appropriate compounds of formula (V) and (VI) are notisolated but are converted in-situ to compounds of formula (I).

Favourably, for the preparation of compounds of formula (I) wherein Xrepresents --NR^(o) ; the appropriate compounds of formula (V) andformula (VI) are reacted together at an elevated temperature, forexample within the range 80° C. to 130° C., preferably 110° C., in anysuitable solvent; the reaction is preferably carried out using theappropriate compound of formula (VI) as solvent in the presence of acatalytic amount of carbon disulphide; preferably the reaction iscarried out under an atmosphere of nitrogen. It will be understood thatunder the abovementioned conditions the compound of formula (IV)initially formed undergoes cyclisation to give the compound of formula(I).

Thus in an alternative aspect the present invention provides a processfor the preparation of a compound of formula (I) wherein X representsNR^(o), which process comprises reacting a compound of the hereinbeforedefined formula (V) providing that X² represents CN, with a compound ofthe hereinbefore defined formula (VI) providing that Y represents NR^(o); and thereafter if required carrying out one or more of the followingoptional steps:

(i) removing any protecting groups;

(ii) converting a compound of formula (I) into a further compound offormula (I);

(iii) converting a compound of formula (I) into a pharmaceuticallyacceptable salt, ester or amide thereof, or a pharmaceuticallyacceptable solvate thereof.

The reaction between compounds of formula (VII) and (VIII) isconveniently carried out in an aprotic solvent, such asdimethylformamide, preferably at a temperature of between 20° C. and 60°C.; the reaction being continued until conventional monitoringtechniques indicate that the reaction is suitably complete.

Suitable hydroxyl and nitrogen protecting groups are those usedconventionally in the art; for example a suitable hydroxyl protectinggroup is a benzyl group.

A preferred nitrogen protecting group R^(h) is a moiety R^(o), asdefined in relation to formula (I), but not including hydrogen.

A compound of formula (I) may be converted into a further compound offormula (I) by using any appropriate conventional method, for examplecompounds wherein R^(o) is hydrogen may be converted into a compoundwherein R^(o) is other than hydrogen by conventional alkylation,arylation, alkanoylation or aralkylation methods. Similarly compounds offormula (I) wherein R^(o) is other than hydrogen may be converted tocompounds of formula (I) wherein R^(o) is hydrogen by conventionaldealkylation, dearylation, dealkanoylation or dearylalkylation methods.Salts, esters, amides and solvates of the compounds of formula (I) maybe prepared using any appropriate conventional procedure compatible withthe nature of the salt, ester, amide or solvate and the compound offormula (I).

Any individual isomer of a compound of formula (I), or apharmaceutically acceptable salt, ester or amide thereof, or apharmaceutically acceptable solvate thereof, may be prepared using anysuitable known method. For example, any mixture of enantiomers may beseparated into individual stereoisomers by using an optically activeacid as a resolving agent. Suitable optically active acids which may beused as resolving agents are described in "Topics in Stereochemistry",Volume 6, Wiley Interscience, 1971, Allinger, N. L. and Eliel, W. L.Eds. When appropriate, the compounds of formula (I) may be separatedinto diastereoisomeric pairs of enantiomers by, for example, fractionalcrystallization from a suitable solvent such as methanol, ethyl acetateor a mixture thereof.

Alternatively, any required enantiomer of a compound of formula (I), ora pharmaceutically acceptable salt, ester or amide thereof, or apharmaceutically acceptable solvate thereof, may be obtained byconventional stereospecific synthesis using optically pure startingmaterials of known configuration.

The absolute stereochemistry of any compound of formula (UI), orsubstrate thereof, may be determined by conventional procedures, such asX-ray crystallography.

The present invention also provides a compound of formula (I), or apharmaceutically acceptable salt, ester or amide thereof, or apharamceutically acceptable solvate thereof, for use as an activetherapeutic substance.

The present invention provides a compound of formula (I), or apharmaceutically acceptable salt, ester or amide thereof, or apharamceutically acceptable solvate thereof, for use in the treatment ofand/or prophylaxis of hyperglycaemia.

In a further aspect the present invention also provides a compound offormula (I) or a pharmaceutically acceptable salt, ester or amidethereof, or a pharmaceutically acceptable solvate thereof, for use inthe treatment and/or prophylaxis of glaucoma and/or the treatment ofdepression and/or for inhibiting blood platelet aggregation.

In a further aspect, the present invention provides a compound offormula (I), or a pharmaceutically acceptable salt, ester or amidethereof, or a pharmaceutically acceptable solvate thereof, for use inthe treatment of hypertension.

A compound of the (I), or a pharmaceutically acceptable salt, ester oramide thereof, or a pharmaceutically acceptable solvate thereof, may beadministered per se or, preferably, as a pharmaceutical composition alsocomprising a pharmaceutically acceptable carrier.

Accordingly, the present invention also provides a pharmaceuticalcomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, ester or amide thereof, or a pharmaceuticallyacceptable solvate thereof, and a pharmaceutically acceptable carriertherefor.

As used herein the term "pharmaceutically acceptable" embracescompounds, compositions and ingredients for both human and veterinaryuse: for example the term "pharmaceutically acceptable salt" embraces aveterinarily acceptable salt.

The composition may, if desired, be in the form of a pack accompanied bywritten or printed instructions for use.

Usually the pharmaceutical compositions of the present invention will beadapted for oral administration, although compositions foradministration by other routes, such as by injection, percutaneousabsorption, and, especially for the treatment and/or prophylaxis ofglaucoma, topical application to the eye, are also envisaged.

Particularly suitable compositions for oral administration are unitdosage forms such as tablets and capsules. Other fixed unit dosageforms, such as powders presented in sachets, may also be used.

In accordance with conventional pharmaceutical practice the carrier maycomprises a diluent, filler, disintegrant, wetting agent, lubricant,colourant, flavourant or other conventional adjuvant.

Typical carriers include, for example, microcrystalline cellulose,starch, sodium starch glycollate, polyvinylpyrrolidone,polyvinylpolypyrrolidone, magnesium stearate, sodium lauryl sulphate orsucrose.

Most suitably the composition will be formulated in unit dose form. Suchunit dose will normally contain an amount of the active ingredient inthe range of from 0.1 to 1000 mg, more usually 0.1 to 500 mg, and moreespecially 0.1 to 250 mg.

As indicated above in relation to the treatment and/or prophylaxis ofglaucoma, a compound of formula (I), or a pharmaceutically acceptablesalt, ester or amide thereof, or a pharmaceutically acceptable solvatethereof, may also be administered as a topical formulation incombination with conventional topical excipients. Such formulations willof course be suitably adapted for administration to the eye.

The topical formulations of the present invention may be presented as,for instance, eye ointments, creams or lotions or eye drops or otherconventional formulations suitable for administration to the eye, andmay contain appropriate conventional additives such as preservatives,solvents to assist drug penetration and emollients in ointments andcreams. The formulations may also contain compatible conventionalcarriers, such as eye ointment, cream or lotion and solvents suitablefor administration to the eye. Such carriers may be present as fromabout 20% up to about 99.5 of the formulation.

Suitable eye ointments, creams or lotions, eye drops or otherconventional formulations suitable for administration to the eye areconventional formulations well known in the art, for example, asdescribed in standard text books of pharmaceutics and cosmetics, such asHarry's Cosmeticology published by Leonard Hill Books, Remington'sPharmaceutical Sciences, and the British and U.S. Pharmacopoeias.

Suitably, the compound of formula (I) or a pharmaceutially acceptablesalt, ester or amide thereof, or a pharmaceutically acceptable solvatethereof, will comprise from about 0.5 to 20% by weight of theformulation, favourably from about 1 to 10% for example 2 to 5%.

The present invention further provides a method for the treatment and/orprophylaxis of hyperglycaemia in a human or non-human mammal whichcomprises administering an effective, non-toxic, amount of a compound ofthe general formula (I), or a pharmaceutically acceptable salt, ester oramide thereof, or a pharmaceutically acceptable solvate thereof, to ahuman or non-human mammal in need thereof.

The present invention further provides a method for the treatment ofhypertension in a human or non-human mammal, which comprisesadministering an effective, non=toxic, amount of a compound of thegeneral formula (I), or a pharmaceutically acceptable salt, ester oramide thereof, or a pharmaceutically acceptable solvate thereof, to ahuman or non-human mammal in need thereof.

The invention also provides a method for the treatment and/orprophylaxis of glaucoma and/or the treatment of depression and/orinhibiting blood platelet aggregation in a human or non-human mammal,which method comprises administering an effective non-toxic amount of acompound of formula (I), or a pharmaceutically acceptable salt, ester oramide thereof, or a pharmaceutically acceptable solvate thereof, to ahuman or non-human mammal in need thereof.

Conveniently, the active ingredient may be administered as apharmaceutical composition hereinbefore defined, and this forms aparticular aspect of the present invention.

In the treatment and/or prophylaxis of hyperglycaemic humans or thetreatment of hypertensive humans the compound of formula (I), or apharmaceutically acceptable salt, ester or amide thereof, or apharmaceutically acceptable solvate thereof, may be taken in doses, suchas those described above, one to six times a day in a manner such thatthe total daily dose for a 70 kg adult will generally be in the range offrom 0.1 to 6000 mg, and more usually about 1 to 1500 mg.

In the treatment and/or prophylaxis of hyperglycaemic non-human mammals,especially dogs, the active ingredient may be adminstered by mouth,usually once or twice a day and in an amount in the range of from about0.025 mg/kg to 25 mg/kg, for example 0.1 mg/kg to 20 mg/kg.

In the treatment and/or prophylaxis of glaucoma (via non-topicalregimes) and the treatment of depression and inhibition of plateletaggregation in human or non-human mammals, dosage regimes are asindicated above for the treatment and/or prophylaxis of hyperglycaemichuman or non-human mammals.

The present invention also provides the use of a compound of formula(I), or a pharmaceutically acceptable salt, ester or amide thereof, or apharmaceutically acceptable solvate thereof, for the manufacture of amedicament for the treatment and/or prophylaxis of hyperglycaemia and/orthe treatment of hypertension.

The present invention further provides the use of a compound of formula(I) or a pharmaceutically acceptable salt, ester or amide thereof, or apharmaceutically acceptable solvate thereof, for the manufacture of amedicament for the treatment and/or prophylaxis of glaucoma and/or thetreatment of depression and/or for the inhibition of blood plateletaggregation.

No toxicological effects are indicated when a compound of formula (I),or a pharmaceutically acceptable salt, ester or amide thereof, or apharmaceutically acceptable solvate thereof, is administered in any ofthe abovementioned dosage ranges.

The following Examples illustrate the invention but do not limit it inany way.

A summary of the examples of the invention are shown below:

    ______________________________________                                         ##STR10##                                                                    Ex.                                                                           No.  Z           A.sup.1       A.sup.2                                                                            X    p   q                                ______________________________________                                              ##STR11##                                                                                 ##STR12##                                                                                   ##STR13##                                                                         NH   2   1                                2                                                                                   ##STR14##                                                                                 ##STR15##                                                                                   ##STR16##                                                                         NH   2   1                                3                                                                                   ##STR17##                                                                                 ##STR18##                                                                                   ##STR19##                                                                         NH   2   1                                4                                                                                   ##STR20##                                                                                 ##STR21##                                                                                   ##STR22##                                                                         NH   2   1                                5                                                                                   ##STR23##                                                                                 ##STR24##                                                                                   ##STR25##                                                                         NH   2   1                                6                                                                                   ##STR26##                                                                                 ##STR27##                                                                                   ##STR28##                                                                         NH   2   1                                7                                                                                   ##STR29##                                                                                 ##STR30##                                                                                   ##STR31##                                                                         NH   2   1                                8                                                                                   ##STR32##                                                                                 ##STR33##                                                                                   ##STR34##                                                                         NH   2   1                                9                                                                                   ##STR35##                                                                                 ##STR36##                                                                                   ##STR37##                                                                         NH   2   1                                10                                                                                  ##STR38##                                                                                 ##STR39##                                                                                   ##STR40##                                                                         NH   2   1                                11                                                                                  ##STR41##                                                                                 ##STR42##                                                                                   ##STR43##                                                                         NH   2   1                                12                                                                                  ##STR44##                                                                                 ##STR45##                                                                                   ##STR46##                                                                         NH   2   1                                13                                                                                  ##STR47##                                                                                 ##STR48##                                                                                   ##STR49##                                                                         NH   2   1                                ______________________________________                                    

EXAMPLE 1

2-[2H-(1-Methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole

A mixture of 3.44 g (20 mM) of 2H-(1-methyl1,3-dihydroisoindole)-2-acetonitrile, 1.22 g (20 mM) of1,2-diaminoethane and a catalytic amount of carbon disulphide was heatedat 110° C. under nitrogen for 6 hours. The mixture was allowed to cooland solidify; 50 ml of water was added to the resultant crystalline massand filtration gave a yellow solid. Recrystallisation from ethyl acetateafforded the title compound as a white solid, m.p. 121°-125° C.(decomp.).

¹ H-nmr δ (CDCl₃): 7.3-7.1 (4H, m), 5.2-4.8 (¹ H, broad m, exchangeswith D₂ O), 4.21 (¹ H, dd), 3.91 (¹ H, q), 3.8-3.5 (6H, m); 3.40 (1H,d); 1.41 (3H, d).

IR (KBr): 1612 cm⁻¹

EXAMPLE 2

2-[2H-(1-Ethyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazoledihydrochloride

This compound was prepared in an analogous manner to Example 1 from 3.72g (20 mM) of 2H-(1-ethyl-1,3-dihydroisoindole)-2-acetonitrile and 1.22 g(20 mM) of 1,2-diaminoethane. The resultant crude product was dissolvedin ethanol and treated with dry hydrogen chloride. The title compoundcrystallised from solution on cooling, m.p. 182°-184° C.

¹ H-nmr δ (DMSO) 11.0-10.5 (3H, broad s, exchanges with D₂ O); 7.5-7.2(4H,m); 4.7-4.6 (1H,m); 4.4-4.1 (2 H,m); 4.0-3.7 (6H,m); 2.2-1.7 (2H,m);0.94 (3H,t).

EXAMPLE 3

2-[2H-(5-Chloro-1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazoledihydrochloride

This compound was prepared in an analogous manner to Example 1 from 3.50g (20 mM) of 2H-(5-chloro-1-methyl-1,3-dihydroisoindole)-2-acetonitrileand 1.22 g (20 mmol) of 1,2-diaminoethane to give the title compound,m.p. 152°-3° C. (isopropanol/ethyl acetate).

¹ H-nmr δ (DMSO)

10.7-10.4 (3H, broad s, exchanges with D₂ O); 7.5-7.2 (3H,m); 4.5-4.0(5H, m); 3.88 (4H,s); 1.52 (3H, d).

EXAMPLE 4

2-[2H-(6-Chloro-1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole.

This compound was prepared in an analogous manner to Example 1 from 2.50g (12 mM) of 2H-(6-chloro-1-methyl-1,3-dihydroisoindole)-2-acetonitrileand 1.1 g (18 mM) of 1,2-diaminoethane to yield the title compound, m.p.158°-160° C. (ethyl acetate).

¹ H-nmr δ (CDCl₃) 7.3-7.0 (3H, m); 5.0-4.5 (1H, broad s exchanges withD₂ O); 4.24 (1H,d); 3.95 (1H,q); 3.7-3.5 (6H, m); 3.41 (1H,d); 1.39(3H,d).

EXAMPLE 5

2[2H-(5-Fluoro-1-methyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole

This compound was prepared in an analogous manner to Example 1 from 2.11g (11 mM) of 2H-(5-fluoro-1-methyl-1,3-dihydroisoindole)-2-acetonitrileand 1.1 g (18 mM) of 1,2-diaminoethane to yield the title compound, m.p.120°-122° C. (ethyl acetate).

¹ H-nmr δ (CDCl₃) 7.3-7.0 (1H,m); 6.9-6.8 (2H,m); 5.0-4.5 (1H broad sexchanges with D₂ O); 4.17 (1H,d); 3.78 (1H,q); 3.7-3.5 (6H,m); 3.40(1H,d); 1.39 (3H,d).

EXAMPLE 6

2-[2H-(1-(4-Chlorophenyl)-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole

The title compound, m.p. 167°-9° C. (ethyl acetate) was prepared from10.5 g (38 mM) of2H-(1-(4-chlorophenyl)-1,3-dihydroisoindole)-2-acetonitrile and 2.43 g(40 mM) of 1,2-diaminoethane by an analogous procedure to that describedin Example 1.

¹ H-nmr δ (DMSO) 6.67-7.6 (8H,m); 5.0 (1H,brs); 4.4 (1H,dd); 3.9 (1H,dd)and 3.35 (6H, brs).

EXAMPLE 7

2-[2H-1-(3-Chlorophenyl)-1,3-dihydroisoindole)methyl]4,5-dihydroimidazole)

The title compound, m.p. 159°-160° C. (ethyl acetate) was prepared from14.7 g (54 mM) of2H-1[1-(3-chlorophenyl)-1,3-dihydroisoindole]-2-acetonitrile and 3.4 g(57 mM) of 1,2-diaminoethane by an analogous procedure to that describedin Example 1.

¹ H nmr δ (CDCl₃) 6.65-7.45 (8H, m); 4.8 (1H, brs); 4.55 (1H, brs,exchanges with D₂ O); 4.4 (1H, dd); 3.85 (1H, dd); 3.48 (2H, s) and 3.4(4H, brs).

EXAMPLE 8

2-[2H-(1-(4-Fluorophenyl)-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole

The title compound, m.p. 168°-169° C. (ethyl acetate) was prepared from7.0 g (27 mM) of2H-(1-(4-fluorophenyl)-1,3-dihydroisoindole)-2-acetonitrile and 1.8 g(30 mM) of 1,2-diaminoethane by an analogous procedure to that describedin Example 1.

¹ H nmr δ (DMSO) 6.65-7.55 (8H, m); 4.8 (1H, brs); 4.5 (1H, brs,exchanges with D₂ O); 4.4 (1H, dd); 3.9 (1H, dd); 3.45 (2H, s) and 3.35(4H, brs).

EXAMPLE 9

2-[2H-(1-Phenyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole

The title compound, m.p. 168°-170° C. (ethyl acetate), was prepared from3.5 g (15 mM) of 2H-(1-phenyl-1,3-dihydroisoindole)-2-acetonitrile and0.9 g (15 mM) of 1,2-diaminoethane by an analogous procedure to thatdescribed in Example 1.

¹ H nmr δ (CDCl₃) 7.4-6.6 (9H, m); 4.75 (1H, brs); 4.35 (1H, dd); 3.82(1H, dd); 3.5 (2H, s) and 3.4 (4H, brs).

EXAMPLE 10

2-(2H-[1-(1-Methylethyl)-1,3-dihydroisoindole]methyl)-4,5-dihydroimidazoledihydrochloride hemihydrate.

This compound was prepared in an analogous manner to Example 1 from 1.0g (5 mM) of 2H-[1-(1-methylethyl)-1,3-dihydroisoindole]-2-acetonitrileand 0.4 ml (7.4 mM) of 1,2-diaminoethane to yield the crude compound.Chromatography over neutral alumina eluting withdichloromethane/methanol (0 3%) yielded an oil. This oil was dissolvedin ethanol and converted to the dihydrochloride with hydrogen chloride.The ethanol was evaporated and residue crystallised from ethanol/ethylacetate to yield the title compound, m.p. 188°-190° C.

¹ H-nmr δ (DMSO) 10.2-10.0 (2H,broad signal, exchanges with D₂ O); 7.27(4H,s); 4.7-4.3 (1H, broad signal, exchanges with D₂ O); 4.47 (1H,d);4.17 (1H,s); 4.00 (1H,d); 3.6-3.4 (6H,m); 2.2-2.20 (1H,m); 0.93 (3H,d);0,89 (3H,d).

EXAMPLE 11

2-[2H-(1-(4-Methylphenyl)-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole

The title compound, m.p. 158°-160° C. (ethyl acetate), was prepared from10.3 g (41 mM) of2H-(1-(4-methylphenyl)-1,3-dihydroisoindole)-2-acetonitrile and 2.7 g(45 mM) of 1,2-diaminoethane by an analogous procedure to that describedin Example 1.

¹ H-nmr δ (DMSO+CDCl₃) 6.6-7.45 (8H,m); 4.8 (1H,brs); 4.35 (1H,dd); 3.82(1H,dd); 3.38 (6H,brs) and 2.3 (3H,s).

EXAMPLE 12

2-[2H-(1-(4-Methoxyphenyl)-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole.The title compound, m.p. 162°-163° C. (ethyl acetate), was prepared from10.4 g (39 mM) of2H-(1-methoxyphenyl)-1,3-dihydroisoindole)-2-acetonitrile and 2.6 g (43mM) of 1,2-diaminoethane by an analogous procedure to that described inExample 1.

¹ H-nmr δ (CDCl₃) 6.65-7.4 (8H, m); 4.75 (1H, s); 4.4 (1H, dd); 3.85(1H, dd); 3.8 (3H, s); 3.5 (2H, brs) and 3.4 (4H, brs).

EXAMPLE 13

2-[2H-(1-Benzyl-1,3-dihydroisoindole)methyl]-4,5-dihydroimidazole.

The title compound, m.p. 132°-134° C. (ethyl acetate), was prepared from4 g (16 mM) of 2H-(1-benzyl-1,3-dihydroisoindole)-2-acetonitrile and 1.1g (18 mM) of 1,2diaminoethane by an analogous procedure to thatdescribed in Example 1.

¹ H nmr δ (CDCl₃) 7.35-7.0 (9H, m), 4.25 (2H, m); 3.75 (1H, d), 3.55(4H, brs); 3.4 (2H, q) and 3.05 (2H, d).

EXAMPLE X1

1-(1-hydroxyethyl)-2-hydroxymethylbenzene

To a suspension of 12 g of lithium aluminium hydride in 50 ml of drydiethyl ether was added dropwise with stirring a solution of 25 g (152.4mM) of 2-acetylbenzoic acid in 120 ml of dry tetrahydrofuran. Afterheating under reflux for 6 hours, the mixture was cooled and treatedcarefully with 12 ml of water, 12 ml of 10% sodium hydroxide solutionand 24 ml of water. The solution was filtered, the filtrate was driedover magnesium sulphate, filtered and evaporated to yield the titlecompound as a colourless waxy solid.

¹ H nmr δ (CDCl₃)

7.4-7.0 (4H,m); 4.9(1H,q); 4.48(1H, broad s); 3.98(2H, broad s,exchanges with D₂ O); 1.4(3H,d).

EXAMPLE X2

1-(1-Bromoethyl)-2-bromomethyl benzene

To a solution of 22 g (144.7 mM) of1-(1-hydroxyethyl)-2-hydroxymethylbenzene in 150 ml of dry diethyl etherwas added dropwise with stirring 58 ml (611 mM) of phosphoroustribromide in 250 ml of diethyl ether while the temperature of thereaction was kept below 30° C. After stirring at room temperature for 18hours the resultant solution was poured into ice/water (500 ml). Theaqueous layer was saturated with sodium chloride and the organic layerseparated, dried and evaporated to yield the title compound bp.115°-117° C./0.5 mm.

¹ H-nmr δ (CDCl₃).

7.8-7.4 (1H, m); 7.4-7.2 (3H, m); 5.60 (1H, q); 4.78 (1H, d); 4.39 (1H,d); 2.05 (3H, d).

EXAMPLE X3

2H-(1-Methyl-1,3-dihydroisoindole)-2-acetonitrile

To a mixture of 10 g (108 mM) of aminoacetonitrile hydrochloride and 40ml (294 mM) of triethylamine in 200 ml of dry dimethylformamide at 50°C. under nitrogen was added dropwise with stirring 27 g (97 mM)1-(1-bromoethyl-2-bromomethylbenzene in 100 ml of dry dimethylformamide.The reaction temperature was kept below 60° C. during the addition.After stirring overnight at room temperature the mixture was poured into600 ml of water, the organic product was extracted with 3×500 mlportions of diethyl ether. The organic layer was washed with water (×1)and saturated sodium chloride solution (×1), dried and evaporated toyield the crude nitrile. Vacuum distillation afforded the title compoundas a pale yellow oil, b.p. 108°-112° C. 0.4 mm.

¹ H-nmr δ (CDCl₃). 7.4-7.0 (4H, m); 4.3-3.7 (3H, m); 3.75 (2H, s); 1.39(3H, d).

EXAMPLE X 4

1-(1-Hydroxypropyl)-2-hydroxymethylbenzene

This compound was prepared in an analogous manner to Example XI from 10g (56 mM) of propiophenone-2-carboxylic acid and lithium aluminiumhydride to yield the title compound as an oil. ¹ H-nmr δ (CDCl₃) 7.5-7.2(4H, m); 4.8-4.5 (3H,m); 3.9-3.5 (2H, broad s, exchanges with D₂ O);1.9-1.6 (2H, m); 0.86 (3H,t).

EXAMPLE X 5

1-(1-bromopropyl)-2-bromomethylbenzene

This compound was prepared in an analogous manner to Example X2 from 7.3g (44 mM) of 1-(1-hydroxypropyl)-2-hydroxymethylbenzene and phosphorustribromide to yield the title compound as a pale yellow oil.

¹ -nmr δ (CDCl₃) 7.5-7.1 (4H,m); 5.31 (1H,t); 4.71 (1H,d); 4.41 (1H, d);2.6-2.1 (2H,m); 1.09 (3H,t).

EXAMPLE X 6

2H-(1-Ethyl-1,3-dihydroisoindole)-2-acetonitrile

This compound was prepared in an analogous manner to Example X3 from 13g (44 mM) of 1-(1-bromopropyl)-2-bromomethylbenzene and 6 g (65 mM) ofaminoacetonitrile hydrochloride to yield the title compound as a palered oil which crystallised on cooling.

¹ H-nmr δ (CDCl₃) 7.4-7.1 (4H,m); 4.24 (1H,d), 4.2-4.0 (1H,m); 3.98(1H,d); 3.72 (2H,s); 2.0-1.7 (2H,m); 0.85 (3H,t).

EXAMPLE X 7

4-Chloro-1-(1-hydroxyethyl)-2-hydroxymethylbenzene

This compound was prepared in an analogous manner to Example X1 from 6.0g (32.8 mM) of 4-chloro-2-formylacetophenone and litnhum aluminiumhydride to yield the title compound as a colourless oil.

¹ H-nmr δ (CDCl₃) 7.4-71. (3H,m); 4.95 (1H,q); 4.68 (1H,d); 4.38 (1H,d);3.8-3.5 (2H,broad s, exchanges with D₂ O); 1.45 (3H,t).

EXAMPLE X 8

1-(1-Chloroethyl)-2-chloromethyl-4-chlorobenzene

This compound was prepared in an analogous manner to Example X2 from 6.0g (32 mM) of 4-chloro-1-(1-hydroxyethyl)-2-hydroxymethylbenzene usingthionyl chloride instead of phosphorous tribromide, to yield the titlecompound as an oil.

¹ H-nmr δ (CDCl₃) 7.5-7.1 (3H,m); 5.50 (1H,q); 4.88 (1H,d); 4.56 (1H,d),1.98 (3H,d).

EXAMPLE X 9

2H-(5-Chloro-1-methyl-1,3-dihydroisoindole)-2-acetonitrile

This compound was prepared in an analogous manner to Example X3 from 3.0g (13.4 mM) of 1-(1-chloroethyl)-2-chloromethyl-4-chlorobenzene and 2.0g (21mmol) of aminoacetonitrile hydrochloride to yield the titlecompound as a crystalline solid.

¹ H-nmr δ (CDCl₃) 7.3-7.2 (2H,m); 7.05 (1H,d); 4.18 (1H,d); 4.03 (2H,s);3.87 (1H,d); 3.77 (1H,d); 1.40 (3H,d).

EXAMPLE X 10

2-(4-Chloro-2-formylphenyl)-4,4-dimethyl-4,5-dihydrooxazole

To a solution of 16 g (76 mM) of 2-(4-chlorophenyl-4,4-dimethyl-4,5-dihydrooxazole in 60 ml of dry tetrahydrofuran at -78°C. under an inert atmosphere was added dropwise 75 ml of 1.4Msec-butyllithium in hexane. After 1 hour 9.7 ml of freshly distilleddimethylformamide in 20 ml of tetrahydrofuran was added and stirring wascontinued for 2 hours at room temperature. The mixture was poured intowater (200 ml) and extracted with diethylether (2×100 ml), dried andevaporated to yield the crude product. Vacuum distillation, bp 140°-150°C./0.4 mm gave the title compound as a pale yellow oil.

¹ H-nmr δ (CDCl₃) 10.78 (1H,s); 8.0-7.7 (2H,m); 7.6-7,4 (1H,m); 4.11(2H,s); 1.35 (6H,s).

EXAMPLE X 11

2-[4-Chloro-2-(1-hydroxyethyl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole

To a suspension of 0.84 g (35 mM) of magnesium metal in 10 ml of diethylether was added dropwise 2.18 ml (35 mmol) of iodomethane. Once all themagnesium had dissolved the solution was added to 6.3 g (23.5 mmol) of2-(4-chloro-2-formylphenyl)-4,4-dimethyl-4,5-dihydrooxazole in 10 ml ofdiethyl ether at 5° C.

After stirring overnight at room temperature the mixture was poured intowater (200 ml) and extracted with diethyl ether (2×100 ml). Drying andevaporation yielded the title compound as a pale yellow oil.

¹ H-nmr δ (CDCl₃) 7.75 (1H,d); 7.5-7.2 (2H,m); 7.05 (1H exchanges withD₂); 5.00 (1H, q); 4.10 (2H, S); 1.50 (3H, d); 1.34 (6H,s).

EXAMPLE X12

5-Chloro-7-methylphthalide

6.3 g (25 mM) of 2-[4-chloro-2-(1hydroxyethyl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole in 25 ml of 6N hydrochloric acidwas heated for 1.5 hours under reflux in an inert atmosphere. Themixture was cooled and extracted with ethyl acetate. After drying andevaporation of the organic extracts the title compound was obtained as apale yellow solid.

¹ H-nmr δ (CDCl₃) 7.84 (1H, d); 7.6-7.4 (2H,m); 5.42 (1H, q); 1.60(3H,d).

EXAMPLE X 13

5-Chloro-1-(1-hydroxyethyl)-2-hydroxymethylbenzene

This compound was prepared in an analogous manner to Example X1 from 4.6g (25 mM) 5-chloro-7-methylphthalide and lithium aluminium hydride toyield the title compound as an oil.

¹ H-nmr δ (CDCl₃) 7.38 (1H,s); 7.3-7.0 (2H,m); 4.91 (1H,q); 4.62 (1H,d);4.33 (1H,d); 4.0-3.7 (2H,broad s, exchanges with D₂ O); 1.40 (3H,s).

EXAMPLE X 14

1-(1-Bromoethyl)-2-bromomethyl-5-chlorobenzene

This compound was prepared in an analogous manner to Example X2 from 4.0g (21,4 mM) of 5-chloro-1-(1-hydroxyethyl)-2-hydroxymethylbenzene andphosphorous tribromide to yield the title compound as an oil.

¹ H-nmr δ (CDCl₃)

7.58 (1H,s); 7.4-7.1 (2H,m); 5.50 (1H,q); 4.72 (1H,d); 4.39 1H,d); 2.10(3H,d).

EXAMPLE X 15

2H-(6-Chloro-1-methyl-1,3-dihydroisoindole)-2-acetonitrile

This compound was prepared in an analogous manner to Example X3 from 5.0g (16 mM) of 1-(1-bromoethyl)-2-bromomethyl-5-chlorobenzene and 2.0 g(21 mM) of aminoacetonitrile hydrochloride to yield the title compoundas an oil.

¹ H-nmr δ (CDCl₃) 7.3-7.1 (3H,m); 4.3-4.0 (3H, m); 3.91 (1H,d); 3.78(1H,d); 1.40 (3H,d).

EXAMPLE X 16

6-Fluoro-3-methylphthalide

30 g (19.8 mM) of 6-amino-3-methylphthalide dissolved in 250 ml of 6Nhydrochloric acid and 200 ml of acetone at 5° C. was treated portionwisewith 13.7 g (19.8 mM) of sodium nitrite. After stirring for 1.5 hours 55g (550 mM) of sodium tetrafluoroborate in 50 ml of water was added andthe mixture left at 5° C. overnight. The acetone was carefullyevaporated under reduced pressure and the resultant solid filtered anddried under vacuum.

The diazonium tetrafluoroborate obtained was added to 75 ml of, nitrogenpurged, xylene and heated at 130° C. for 0.25 hours. Upon cooling themixture was treated with saturated sodium bicarbonate solution untilalkaline and extracted with diethyl ether (3×50 ml). After drying andevaporation the crude product was obtained as a dark brown oil.Chromatography over silica gel eluting with dichloromethane gave thetitle compound as a low melting solid.

¹ H-nmr δ (CDCl₃) 7.7-7.3 (3H, m); 5.64 (1H,q); 1.72 (3H,d).

EXAMPLE X 17

4-Fluoro-1-(1-hydroxyethyl)-2-hydroxymethylbenzene

This compound was prepared in an analogous manner to Example X1 from 8.0(48 mM) of 6-fluoro-3-methylphthalide and lithium aluminium hydride toyield the title compound as a yellow oil.

¹ H-nmr δ (CDCl.sub. 3)

7.5-7.2 (1H,m); 7.1-6.9 (2H,m); 4.95 (1H,q); 4.65 (1H,d): 4.40 (1H,d);3.9-3.6 (2H,broad s, exchanges with D₂ O); 1.42 (3H,d).

EXAMPLE X 18

1-(1-Bromoethyl)-2-bromomethyl-4-fluorobenzene

This compound was prepared in an analogous manner to Example X2 from 7.5g (544 mM) of 4-fluoro-1-(1-hydroxyethyl)-2-hydroxymethyl benzene andphosphorous tribromide to yield the title compound as an oil whichslowly crystallised at room temperature.

¹ H-nmr δ (CDCl₃)

7.8-7.4 (1H,m); 7.3-6.8 (2H,m); 5.56 (1H,q); 4.75 (1H,d); 4.40 (1H,d);2.10 (3H,d).

EXAMPLE X 19

2H-(5-Fluoro-1-methyl-1,3-dihydroisoindole)-2-acetonitrile

This compound was prepared in an analogous manner to Example X3 from 9.3g (31.4 mM) of 1-(1-bromoethyl)-2-bromomethyl-4-fluorobenzene and 3.0 g(32.4 mM) of aminoacetonitrile hydrochloride to yield the title compoundas a pale yellow oil.

¹ H-nmr δ (CDCl₃) 7.3-6.9 (3H,m); 4.3-3.8 (3H,m); 3.80 (2H,s); 1.35(3H,d).

EXAMPLE X 20

α-(4-Chlorophenyl)-1,2-benzenedimethanol

A mixture of 55 g (0.3M) of 2-(4-chlorobenzoyl) benzoic acid, 5 ml ofconcentrated sulphuric acid and 500 ml of methanol was heated underreflux for 3 hours. The mixture was evaporated and the residue was takenup in dichloromethane washed with water then aqueous sodium bicarbonate.The dichloromethane was dried and evaporated. The residue was thenreduced with lithium aluminium hydride in an analogous manner to thatdescribed in Example X1 to give the title compound.

¹ H nmr δ (CDCl₃) 7.22 (8H, m), 5.72 (1H,s); 4.35 (4H, brs, 2H exchangewith D₂ O).

EXAMPLE X 21

α-(2-Bromomethylphenyl)-4-chlorophenylmethyl bromide

Excess hydrogen bromide was bubbled through a solution of 28 g (0.11M)of α-(4-chlorophenyl)-1,2-benzenedimethanol in 250 ml ofdichloromethane. After stirring for 12 hours at room temperature themixture was dried and evaporated to give the title compound.

¹ H nmr δ (CDCl₃) 7.3 (8H,m); 6.72 (1H,S) and 4.56 (2H,q).

EXAMPLE X 22

2H-(1-(4-Chlorophenyl)-1,3-dihydroisoindole)-2-acetonitrile

The title compound was prepared from 37.3 g (0.11M) ofα-(2-bromomethylphenyl)-4-chlorophenyl methyl bromide, 13.82 g (0.15M)of aminoacetonitrile hydrochloride and 42 ml (0.3M) of triethylamine byan analogous method to that described in Example X3.

¹ H nmr δ (CDCl₃) 6.68-7.53 (8H, m ), 4.92 (1H, brs), 4.2 (2H, m), and3.8 (2H, q).

EXAMPLE X 23

α-(3-Chlorophenyl)-1,2-benzenedimethanol

Excess hydrogen chloride gas was bubbled though a solution of 25 g(0.14M) of 2-(3-chlorobenzoyl)benzoic acid in 1 liter of methanol. Themixture was then stirred at room temperature for 12 hours. The mixturewas evaporated and the residue was taken up in dichloromethane washedwith water then aqueous sodium bicarbonate. The dichloromethane wasdried and evaporated. The residue was then reduced with lithiumaluminium hydride in an analogous manner to that described in Example X1to give the title compound.

¹ H nmr δ (CDCl₃) 7.18 (8H, m); 5.75 (1H, s); 4.35 (4H, brs, 2Hexchanges with D₂ O).

EXAMPLE X 24

α-(2-Bromomethylphenyl)-3-chlorophenylmethyl bromide Excess hydrogenbromide was bubbled through a solution of 21 g (84 mM) ofα-(3-chlorophenyl)-1,2-benzenedimethanol in 250 ml of dichloromethane.After stirring for 12 hours at room temperature the mixture was driedand evaporated to give the title compound.

¹ H nmr δ (CDCl₃) 7.4 (8H, m); 6.65 (1H, s) and 4.53 (2H q).

EXAMPLE X 25

2H-(1-(3-Chlorophenyl)-1,3-dihydroisoindole)-2-acetonitrile

The title compound was prepared from 28 g (74.8 mM) ofα-(2-bromomethylphenyl)-3-chlorophenylmethyl bromide, 11.5 g (0.12m) ofaminoacetonitrile hydrochloride and 34.5 ml (0.25M) of triethylamine byan analogous method to that described in Example X3.

¹ H nmr δ (CDCl₃) 6.68-7.63 (8H,m); 4.85 (1H, brs); 4.25 (2H, m) and3.62 (2H, brs).

EXAMPLE X 26

α-(4-Fluorophenyl)-1,2-benzenedimethanol

Excess hydrogen chloride gas was bubbled through a solution of 50 g of2-(4-fluorobenzoyl) benzoic acid in 1 litre of methanol. The mixture wasthen stirred at room temperature for 12 hours. The mixture wasevaporated and the residue was taken up in dichloromethane washed withwater then aqueous sodium bicarbonate. The dichloromethane was dried andevaporated. The residue in 1 litre of ether was reduced with 5.6 g oflithium borohydride under nitrogen gas. The ether was evaporated and theresidue was partitioned between water and dichloromethane. Thedichloromethane was dried and evaporated to give the title compound.

¹ H nmr δ (CDCl₃) 6.7-7.32 (8H, m); 5.82 (1H, brs) and 4.3 (2H, brs).

EXAMPLE X 27

α-(2-Bromomethylphenyl)-4-fluorophenylmethyl bromide

The title compound was prepared from 40 g (0.17M) ofα-(4-fluorophenyl)-1,2-benzenedimethanol and 40 ml (0.42M) ofphosphorous tribromide in 200 ml of ether by an analogous procedure tothat described in Example X2.

¹ H nmr δ (CDCl₃) 6.78-7.7 (8H, m); 6.83 (1H, s) and 4.5 (2H, q).

EXAMPLE X 28

2H-(1-(4-Fluorophenyl)-1,3-dihydroisoindole)-2-acetonitrile

The title compound was prepared from 52.2 g (0.16M) ofα-(2-bromomethylphenyl)-4-fluorophenyl methylbromide, 16.2 g (0.17M) ofaminoacetonitrile hydrochloride and 62 ml (0.44M) of triethylamine by ananalogous method to that described in Example X3

¹ H nmr δ (CDCl₃) 6.7-7.55 (8H, m); 4.9 (1H, brs); 4.2 (2H,m) and 3.62(2H.brs).

EXAMPLE X 29

2H-(1-Phenyl-1,3-dihydroisoindole)-2-acetonitrile

The title compound, m.p. 106°-107° C. (isopropanol), was prepared from17.4 g (51 mM) of α-(2-bromomethylphenyl) phenylmethyl bromide, 7.1 g,(76 mM) of aminoacetonitrile hydrochloride and 21.5 ml (154 mM) oftriethylamine by an analogous method to that described in Example X 4.

¹ H nmr δ (CDCl₃) 7.4-6.6 (9H,m); 4.85 (1H, brs); 4.25 (2H, m) and 3.68(2H, s).

EXAMPLE X30

1-(1-Methylethyl)phthalide

A mixture of 4 g (22.9 mM) of 1-(1-methylethenyl) phthalide and 50 mg ofAdam's catalyst in 200 ml of ethanol was hydrogenated at atmosphericpressure. After the required amount of hydrogen was consumed the mixturewas filtered and evaporated to yield the title compound as a pale yellowoil.

¹ H - nmr δ (CDCl₃) 8.0-7.4 (4H, m); 5.40 (1H, d); 2.5-7.1 (1H, m); 1.10(3H, d); 0.81 (3H, d).

EXAMPLE X31

1-Hydroxy methyl-2-(1-hydroxy-2-methylpropyl)benzene

This compound was prepared in an analogous manner to Example X1 from 3.9g (22 mM) of 1-(1-methylethyl) phthalide and lithium aluminium hydrideto yield the title compound as an oil.

¹ H - nmr δ (CDCl₃) 7.5-7.0 (4H, m); 4.48 (2H, s); 4.33 (1H, d); 4.0-3.5(2H, broad signal, exchanges with D₂ O); 2.3-1.8 (1H, m); 1.05 (3H, d);0.68 (3H, d).

EXAMPLE X32

1-Bromomethyl-2-(1-bromo-2-methylpropyl)benzene.

This compound was prepared in an analogous manner to Example X2 from 3.5g (19.4 mmol) of 1hydroxymethyl-2-(1-hydroxy-2-methylpropyl)benzene andphosphorus tribromide to yield the title compound as an oil.

¹ H - nmr δ (CDCl₃) 7.6-7.1 (4H, m); 5.05 (1H, d); 4.65 (1H, d); 4.40(1H, d); 2.8-2.3 (1H, m); 1.28 (3H, d); 0.86 (3H, d).

EXAMPLE X33

2H-[1-(1-Methylethyl)-1,3-dihydroisoindole]-2-acetonitrile hydrochloride

This compound was prepared in an analogous manner to Example X3 from 4.8g (15.7 mM) of 1-bromomethyl-2-(1-bromo-2-methylpropyl)benzene and 1.5 g(16.2 mM) of aminoacetonitrile hydrochloride to yield the crude compoundas an oil. This was dissolved in ethyl acetate and converted to thehydrochloride with hydrogen chloride to yield the title compound.

¹ H - nmr δ (DMSO)

11.0-10.5 (1H, broad singlet, exchanges with D₂ O); 7.5-7.2 (4H, m);4.81 (1H, d); 5.50 (1H, d); 4.44 (1H, d); 3.34 (2H, s); 2.5-2.3 (1H, m);1.03 (3H, d); 0.94 (3H, d).

EXAMPLE X34

α-(4-Methylphenyl)-1,2-benzenedimethanol.

The title compound was prepared from 2-(4-methylbenzoyl)benzoic acid byan analogous procedure to that described in Example X26.

¹ H - nmr δ (CDCl₃)

6.9-7.37 (8H, m); 5.9 (1H, brs); 4.3 (2H, m) and 2.3 (3H, s).

EXAMPLE X35

α-(2-Bromomethylphenyl)-4-methylphenylmethyl bromide.

The title compound was prepared from 52 g (0.23M) ofα-(4-methylphenyl)-1,2-benzenedimethanol and 50 ml (0.53M) of phosphorustribomide in 1 liter of diethyl ether by an analogous procedure to thatdescribed in Example X2.

¹ H - nmr δ (CDCl₃)

6.88-7.8 (8H, m); 6.7 (1H, s); 4.5 (2H, q) and 2.27 (3H, s).

EXAMPLE X36

2H-(1-(4-Methylphenyl)-1,3-dihydroisoindole)-2-acetonitrile.

The title compound was prepared from 70 g (0.2M) ofα-(2-bromomethylphenyl)-4-methylphenylmethyl bromide, 22 g (0.23M) ofaminoacetonitrile hydrochloride and 83 ml (0.6M) of triethylamine by ananalogous method to that described in Example X3.

¹ H - nmr δ (CDCl₃)

6.7-7.6 (8H, m); 4.83 (1H, brs); 4.15 (2H, m) 3.6 (2H, m) and 2.18 (3H,s).

EXAMPLE X37

α-(4-Methoxyphenyl)-1,2-benzenedimethanol.

The title compound was prepared from 2-(4-methoxybenzoyl)benzoic acid byan analogous procedure to that described in Example X26.

¹ H - nmr δ (CDCl₃)

6.7-7.3 (8H, m); 5.73 (1H, brs); 4.3 (2H, brs) and 3.63 (3H, s).

EXAMPLE X38

α-(2-Bromomethylphenyl)-4-methoxyphenylmethyl bromide.

The title compound was prepared from 50 g (0.2M) ofα-(4-methoxyphenyl)-1,2-benzenedimethanol and 50 ml (0.53M) ofphosphorus tribromide in 1 liter of diethyl ether by an analogousprocedure to that described in Example X2.

¹ H - nmr δ (CDCl₃)

6.85-7.9 (8H, m); 6.7 (1H, s); 4.4 (2H, q) and 3.7 (3H, s).

EXAMPLE X39

2H-(1-(4-Methoxyphenyl)-1,3-dihydroisoindole)-2-acetonitrile.

The title compound was prepared from 53 g (0.14M) ofα-(2-bromomethylphenyl)-4-methoxyphenylmethyl bromide, 16 g (0.17M) ofaminoacetonitrile hydrochloride and 60 ml (0.43M) of triethylamine by ananalogous method to that described in Example X3.

¹ H - nmr δ (CDCl₃)

6.5-7.5 (8H, m); 4.9 (1H, brs); 4.2 (2H, m) and 3.7 (5H, m+s).

EXAMPLE X40

1-(Bromomethyl)-2-(2-phenyl-1-bromoethyl)benzene.

The title compound was prepared from 12.5 g (55 mM) of(1-hydroxymethyl)-2-(2-phenyl-1-hydroxyethyl)benzene and 5.7 ml (60 mM)of phosphorus tribromide in chloroform (150 ml) by an analogousprocedure to that described in Example X2.

¹ H - nmr δ (CDCl₃)

7.9-6.85 (9H, m); 5.5 (1H, t); 4.35 (2H, q) and 3.5 (2H, d).

EXAMPLE X41

2H-(1-Benzyl-1,3-dihydroisoindole)-2-acetonitrile

The title compound, m.p. 78°-79° C. (isopropanol), was prepared from19.8 g (56 mM) of 1-(bromomethyl)-2-(2-phenyl-1-bromoethyl)benzene, 7.8g (84 mM) of amino acetonitrile hydrochloride and 23.4 ml (16.8 mM)triethylamine by an analogous method to that described in Example X4.

¹ H - nmr δ (CDCl₃)

7.4-7.1 (9H, m); 4.4 (1H, m); 4.3 (1H, dd); 4.05 (1H, dd); 3.5 (1H, d);3.25 (2H, m); and 2.8 (1H, dd).

DEMONSTRATION OF EFFECTIVENESS OF COMPOUNDS (A) Reversal ofAdrenaline-Exacerbated Glucose Intolerance in Mice

CFLP female mice of about 25 g were fasted for 24 hours prior toreceiving water (10 ml/kg) or compounds by oral gavage. Thirty minuteslater, glucose (1 g/kg) and adrenaline (300 μg/kg) were injectedsubcutaneously. Blood samples for glucose analysis were taken seriallyfrom the tail of each mouse at 0, 30, 60 90 and 120 minutes after dosingglucose and the results are expressed below as the percentage reductionin the area under the blood glucose curve; the compound treated groupsbeing compared to the water dosed control group. Six mice were used ineach treatment group.

    ______________________________________                                                               % Reduction in area                                                 Dose      under Blood Glucose                                    Example No:  (μmol/kg)                                                                            curve                                                  ______________________________________                                        1            20        34                                                     2            20        27                                                     3            10        41                                                     4            20        27                                                     5             5        20                                                     6            20        15                                                     7            20        22                                                     8            20        21                                                     9            20        31                                                     12           20        34                                                     13           20        16                                                     ______________________________________                                    

α₂ -Adrenoceptor Binding

Human platelet membranes were incubated with [³ H] Rauwolscine (0.5-1.0nM) for 30 minutes at 30° C. with varying concentrates of the drug(0.1-10,000 nM). The binding assay was stopped by filtering and rinsingon GF/B glass fibre filters.

    ______________________________________                                                      Binding Affinity                                                Example No:   Ki (nM)                                                         ______________________________________                                        1             1.7                                                             2             4.1                                                             3             3.4                                                             4             6.4                                                             5             0.8                                                             6             3.6                                                             7             1.8                                                             8             2.7                                                             9             6.9                                                             10            34.0                                                            11            25.0                                                            12            2.0                                                             13            40.0                                                            ______________________________________                                    

We claim:
 1. A compound of formula (I): ##STR50## or a pharmaceuticallyacceptable salt, ester or amide thereof, or a pharmaceuticallyacceptable solvate thereof, wherein:Z represent a residue of asubstituted or unsubstituted phenyl or naphthyl group; A¹ represents asubstituted or unsubstituted methylene group; A² represents asubstituted or unsubstituted methylene group; providing that at leastone of A¹ and A² represents a substituted methylene group, substituentsfor A¹ and A² are selected from C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl, C₂₋₁₂-alknyl, phenyl, naphthyl, phenyl-C₁₋₁₂ -alkyl or naphthyl-C₁₋₁₂ -alkyl,each of which is independently substituted or unsubstituted; Xrepresents NR^(O) wherein R^(O) represents a hydrogen atom, asubstituted or unsubstitited C₁₋₁₂ -alkyl group, a substituted orunsubstituted phenyl or naphthyl group, a C₁₋₁₂ -alkanoyl groupsubstituted or unsubstituted in the alkyl moiety, or a phenyl- ornaphthyl-C₁₋₁₂ -alkyl moiety substituted or unsubstituted in the arylmoiety; p represents the integer 3; q represents an integer in the rangeof from 1 to 12; and wherein optional substituents for any of saidphenyl, naphthyl, alkyl, alkenyl, or alkynyl groups of moieties arehalogen, C₁₋₁₂ -alkyl, C₂₋₁₂ -alkenyl, C₂₋₁₂ -alkynyl, phenyl,halo-C₁₋₁₂ -alkyl, hydroxy, C₁₋₁₂ -alkoxy, phenyl-C₁₋₁₂ -alkoxy,naphthyl-C₁₋₁₂ -alkoxy, amino, mono- and di-C₁₋₁₂ -alkylamino,amino-C₁₋₁₂ -alkyl, mono- and di-C₁₋₁₂ -alkylamino-C₁₋₁₂ -alkyl, nitro,carboxy, C₁₋₁₂ -alkoxycarbonyl, carboxy-C₁₋₁₂ -alkyl, C₁₋₁₂-alkoxycarbonyl-C₁₋₁₂ -alkyl, C₁₋₁₂ -alkylcarbonyl, or a moiety SO₂NR^(s) R^(t) wherein R^(s) and R^(t) each independently representhydrogen or C₁₋₁₂ -alkyl or R^(s) and R^(t) together with the nitrogento which they are attached form a saturated 5- or 6-membered ring.
 2. Acompound, according to claim 1, wherein Z represents the residue of asubstituted or unsubstituted phenyl group.
 3. A compound, according toclaim 1, wherein A¹ represents a substituted methylene group and A²represents an unsubstituted methylene group.
 4. A compound, according toclaim 1, of formula (II): ##STR51## or a pharmaceutically acceptablesalt, ester or amide thereof, or a pharmaceutically acceptable solvatethereof, wherein:Z, X, p and q are as defined in relation to formula(I), R and R¹ each independently represents hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted phenyl, naphthyl,phenylalkyl, or naphthylalkyl substituted or unsubstituted in the phenylor naphthyl moiety; providing that only one of R and R¹ representshydrogen.
 5. A compound, according to claim 4, wherein R and R¹ eachindependently represents hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted phenyl, naphthyl, phenylalkyl, ornaphthylalkyl.
 6. A compound, according to claim 4, wherein R¹represents hydrogen.
 7. A compound, according to claim 4, wherein Rrepresents alkyl, substituted or unsubstituted phenyl or a benzyl groupand R¹ represents hydrogen.
 8. A compound, according to claim 4, offormula (III): ##STR52## or a pharmaceutically acceptable salt, ester oramide thereof, or a pharmaceutically acceptable solvate thereof; whereinR, R¹, X, p and q are as defined above and R² and R³ each independentlyrepresents hydrogen, alkyl, amino, mono- or di- alkyl amino, hydroxy,alkoxy, carboxy, or a halogen atom.
 9. A compound, according to claim 8,wherein R² represents halogen and R³ represents hydrogen.
 10. Acompound, according to claim 8, wherein R² and R³ both representhydrogen.
 11. A compound, according to claim 1, wherein X representsNR^(O).
 12. A compound, according to claim 1, wherein X represents NH.13. A compound, according to claim 1, wherein q represents theinteger
 1. 14. A pharmaceutical composition comprising a compound offormula (I) as defined in claim 1, or a pharmaceutically acceptablesalt, ester or amide thereof, or a pharmaceutically acceptable solvatethereof, and a pharmaceutically acceptable carrier therefor.
 15. Amethod for the treatment or prophylaxis of hyperglycaemia orhypertension in a human or non-human mammal which comprisesadministering an effective non-toxic, amount of a compound of formula(I) as defined in claim 1, or a pharmaceutically acceptable salt, esteror amide thereof, or a pharmaceutically acceptable solvate thereof, to ahuman or non-human mammal in need thereof.
 16. A method for thetreatment or prophylaxis of glaucoma or the treatment or prophylaxis ofinhibiting blood platelet aggregation in a human or non-human mammal,which method comprises administering an effective non-toxic, amount of acompound of formula (I) as defined in claim 1, or a pharmaceuticallyacceptable salt, ester or amide thereof, or a pharmaceuticallyacceptable solvate thereof, to a human or non-human mammal in needthereof.